(1r,4r)-4-({2-carbamoyl-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}amino)cyclohexyl 2-aminoacetate

• ChemBase编号: 73164
• 分子式: C25H30F3N5O4
• 平均质量: 521.5320096
• 单一同位素质量: 521.22498913
• SMILES: n1(c2c(c(n1)C(F)(F)F)C(=O)CC(C2)(C)C)c1ccc(c(c1)N[C@@H]1CC[C@H](CC1)OC(=O)CN)C(=O)N
• Canonical SMILES: NCC(=O)O[C@@H]1CC[C@H](CC1)Nc1cc(ccc1C(=O)N)n1nc(c2c1CC(C)(C)CC2=O)C(F)(F)F
• InChI: InChI=1S/C25H30F3N5O4/c1-24(2)10-18-21(19(34)11-24)22(25(26,27)28)32-33(18)14-5-8-16(23(30)36)17(9-14)31-13-3-6-15(7-4-13)37-20(35)12-29/h5,8-9,13,15,31H,3-4,6-7,10-12,29H2,1-2H3,(H2,30,36)/t13-,15-
• InChIKey: AVDSOVJPJZVBTC-CTYIDZIISA-N

名称和登记号

名称

• IUPAC标准名: (1r,4r)-4-({2-carbamoyl-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}amino)cyclohexyl 2-aminoacetate
• IUPAC传统名: (1r,4r)-4-({2-carbamoyl-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-5,7-dihydroindazol-1-yl]phenyl}amino)cyclohexyl 2-aminoacetate
• 别名: SNX-5422; PF-04929113

登记号

• CAS号: 908115-27-5
• PubChem SID: 162038084
• PubChem CID: 44195571

理论计算性质

• Acid pKa: 15.169958
• 质子受体: 6
• 质子供体: 3
• LogD (pH = 5.5): 1.2991843
• LogD (pH = 7.4): 2.7121146
• Log P: 2.8847678
• 摩尔折射率: 131.8124 cm^3
• 极化性: 49.19859 Å^3
• 极化表面积: 142.33 Å^2
• 可自由旋转的化学键: 8
• 里宾斯基五规则: false

分子性质

安全信息

• 保存条件: -20°C

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S2656

Research Area

• Description: Cancer

Biological Activity

• Description: PF-04929113 (SNX-5422) is a potent and selective HSP90 inhibitor with K_d of 41 nM and also inhibits Her-2 degradation with IC50 of 37 nM.
• Targets: HSP90; Her-2
• IC50: 41 nM (K_d); 37 nM ^[1]
• In Vitro: PF-04929113 is a small-molecule Hsp90 inhibitor based on the 6,7-dihydro-indazol-4-one scaffold. PF-04929113 developed by Serenex, converts to SNX-2122, which is the active Hsp90 inhibitor form. PF-04929113 exhibits potent effects on Her-2 stability and causes expected up-regulation of Hsp70. PF-04929113 shows potent antiproliferative activity against a broad range of cancer cell types, e.g. MCF-7 (IC50=16 nM), SW620 (IC50=19 nM), K562 (IC50=23 nM), SK-MEL-5 (IC50=25 nM), and A375 (IC50=51 nM). ^[1]
• In Vivo: PF-04929113 inhibits human MM cell growth in vivo, and immuno-histochemical analysis shows PF-04929113 significantly inhibits p-ERK and p-Akt in treated mice. Meanwhile, PF-04929113 treatment significantly decreases the percentage of CD31+ cells and MVD, consistent with an inhibitory effect on angiogenesis in vivo. A 50 mg/kg administration of PF-04929113 delivered 3 times per week significantly delays castrate-resistant LNCaP tumor growth and prolongs cancer specific survival. ^[2] Immuno-histochemical analysis indicates increased SP70 expression, and decreases Ki67, Akt, and AR expression, after treatment with PF-04929113. Inhibition of tumor progression by PF-04929113 may result from a combination of decreased proliferative (reduced Ki67 and Akt expression) or increased apoptosis (increased ApopTag staining) rates. ^[3]
• Clinical Trials: PF-04929113 is currently under the Phase I clinical trial for the safety and pharmacology study in subjects with refractory solid tumor malignancies.

Combination Therapy

• Description: Treatment of PF-04929113 combined with OGX-011, an antisense drug that targets clusterin, in xenograft models of human castrate-resistant prostate cancer shows that OGX-011 markedly potentiates antitumor efficacy, leading to an 80% inhibition of tumor growth with prolonged survival compared with PF-04929113 monotherapy. ^[4]

Protocol

• Protocol: Kinase Assay ^[1]
• Affinity for Hsp90: Hsp90 from porcine spleen extract is isolated by affinity capture on a purine-affinity media. The Hsp90 loaded media is then challenged with PF-04929113 at a given concentration, ranging from 0.8 to 500 μM, and the amount of Hsp90 liberated at each concentration is determined by Bradford protein assay. The resulting IC50 values are corrected for the ATP ligand concentration and presented as apparent K_d values.
• Protocol: Cell Assay ^[1]
• Cell Lines: MCF-7, SW620, K562, SK-MEL-5 and A375 cancer cell lines
• Concentrations: 0-300 nM
• Incubation Time: 72 or 144 hours
• Methods: All assays are done in 96-well plates. All cell lines are purchased from ATCC. Proliferation rates are measured by seeding cells into 96-well plates, followed by compound addition 24 h later. After addition of PF-04929113, cells are allowed to grow for either an additional 72 or 144 h depending on rate of growth. At harvest, media is removed and DNA content for individual wells is determined using CyQuant DNA dye. Levels of Hsp90 client proteins and phosphor-regulated proteins in A375 are measured by high content analysis (HCA) using an ArrayScan 4.5 instrument after 24 hours of treatment with PF-04929113, followed by methanol fixation. After fixation in 4% PBS-buffered formalin and permeablization with 0.1% TX-100, cells are probed with anti-Her2, antiphospho-S6 (pS6), antipERK, and anti-Hsp70 primary antibodies, followed by TRITC or FITC conjugated secondary antibodies. Nuclei are also stained with Hoechst DNA binding dye. For each well, 250-500 individual nuclei are identified along with the average staining intensity for the client and phospho-proteins for each cell. Average client staining intensities are then calculated for each well.
• Protocol: Animal Study ^[2]
• Animal Models: 5 × 10^6 MM.1S cells are inoculated subcutaneously in the Fox Chase SCID mice (6-7 weeks old).
• Formulation: PF-04929113 is dissolved in 1% carboxy methylcellulose/0.5% Tween 80 at 10 mg/mL and stored at 4 °C for in vivo study.
• Doses: 20 or 40 mg/kg
• Administration: PF-04929113 is administered orally 3 times per week, total 3 weeks.

References

• References: [1] Huang KH, et al, J Med Chem, 2009, 52(14), 4288-4305
• References: [2] Yutaka Okawa, et al, Blood, 2009, 113(4), 846-855.
• References: [3] Lamoureux F, et al, Clin Cancer Res, 2011, 17(8), 2301-2313.
• References: [4] Jain L, et al, J Chromatogr B Analyt Technol Biomed Life Sci, 2010, 878(30), 3187-3192.

参考文献

• Huang KH, et al, J Med Chem, 2009, 52(14), 4288-4305
• Yutaka Okawa, et al, Blood, 2009, 113(4), 846-855.
• Lamoureux F, et al, Clin Cancer Res, 2011, 17(8), 2301-2313.
• Jain L, et al, J Chromatogr B Analyt Technol Biomed Life Sci, 2010, 878(30), 3187-3192.